Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats

Abstract

AZMCAO) for 2h followed by varying time points of reperfusion. The brain loci specific and time dependent alterations were seen in the expression pattern of molecular markers i.e. heat-shock protein 70 (HSP70) for cytoplasmic dysfunction, glucose-regulated protein 78 (GRP78), Caspase-12, C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153), activating transcription factor 4 (ATF-4) and Processed X-box protein 1 (xbp1) mRNA for ER dysfunction. Histological examinations indicated pronounced brain damage, massive neuronal loss and DNA fragmentation predominantly in the striatum and cortex. The enhanced expression of GRP78, Caspase-12, CHOP/GADD153, ATF4 and processing of xbp1 mRNA in the affected brain loci indicate the critical involvement of ER mediated cell death/survival mechanisms and also collectively demonstrated the activation of UPR signaling pathways i.e. PERK and IRE1. Further, Salubrinal, a selective inhibitor of eIF2α dephosphorylation was used to counteract ER stress, which significantly increased the phosphorylation of eIF2α, leading to reduced brain damage after I/R injury. Therefore, inhibition of ER stress following I/R injury may be used as therapeutic target for neuroprotection.